The skin is one of the most readily accessible organs of the human body, covering a surface area of approximately 2 m2 and receiving about one third of the body's blood circulation. The skin is a complex system consisting of the epidermis, the dermis, and skin appendages, such as hairs, interwoven within the two layers. The outermost layer of the skin, the epidermis, is avascular, receiving nutrients from the underlying dermal capillaries by diffusion through a basement membrane. The outermost layer of the epidermis is called the stratum corneum, the protective covering that serves as a barrier to prevent desiccation of the underlying tissues and to exclude the entry of noxious substances from the environment, including agents applied to the skin. This layer consists of corneocytes embedded in lipid regions.
Transdermal (or transcutaneous) drug delivery offers advantages over traditional drug delivery methods, such as injections and oral delivery. In particular, transdermal drug delivery avoids gastrointestinal drug metabolism, reduces side-effects and can provide sustained release of therapeutic compounds. The term “transdermal” is used generically because, in reality, transport of compounds by passive diffusion occurs only across the epidermis where absorption into the blood via capillaries occurs.
However, the diffusion rate of topically applied compounds will vary because of both internal (physiological) and external (environmental) factors. The diffusion rate is also dependent upon physical and chemical properties of the compounds being delivered. The patient's skin needs to be carefully evaluated to minimize the natural, internal barriers to transdermal drug delivery (e.g. dry skin, thick skin, dehydration, poor circulation, poor metabolism) and to maximize the natural enhancers (e.g. ensuring the patient is well hydrated and selecting an area of skin that is thin, warm, moist, and well perfused). The stratum corneum is considered to be the rate-limiting barrier for transdermal delivery and so diffusion is often enhanced. Various methods include preheating the skin to increase kinetic energy and dilate hair follicles, and covering the area with an occlusive dressing after the drug application to maintain moisture and activate the reservoir capacity of the skin.
Enhancers of transcutaneous drugs are usually used to alter the nature of the stratum corneum to ease diffusion. This alteration may result from denaturing the structural keratin proteins in the stratum corneum, stripping or delaminating the cornified layers of the stratum corneum, changing cell permeability, or altering the lipid-enriched intercellular structure between corneocytes. Enhancers are incorporated into transdermal-controlled drug delivery systems, or they are used prior to, during, or after the topical application of a drug. Preferred enhancers allow drugs to diffuse actively and quickly, but do not inactivate the drug molecules, damage healthy epidermis, cause pain, or have toxicological side effects.
Even though ultrasound has been used extensively for medical diagnostics and physical therapy, it has only recently become popular as an enhancer of drug delivery. Numerous studies have demonstrated that ultrasound is generally safe, with no negative long-term or short-term side effects, but the mechanisms by which ultrasound works as an enhancer are less clearly understood.
Ultrasound is defined as sound at a frequency of between 20 kHz and 10 MHz. The properties defining the ultrasound are the amplitude and the frequency of the sound waves. Similar to audible sound, ultrasound waves undergo reflection, refraction, or absorption when they encounter another medium with dissimilar properties. If the properties of the encountered medium are different from those of the transmitting medium, the acoustic energy of the transmitted ultrasound beam is attenuated by being absorbed or dissipated. Attenuation of ultrasound in tissue limits its depth of penetration.
Both the thermal and non-thermal characteristics of high-frequency sound waves can enhance the diffusion of topically applied drugs. Heating from ultrasound increases the kinetic energy of the molecules (mobility) in the drug and in the cell membrane, dilates points of entry such as the hair follicles and the sweat glands, and increases the circulation to the treated area. These physiological changes enhance the opportunity for drug molecules to diffuse through the stratum corneum and be collected by the capillary network in the dermis. Both the thermal and non-thermal effects of ultrasound increase cell permeability. The mechanical characteristics of the sound wave also enhance drug diffusion by oscillating the cells at high speed, changing the resting potential of the cell membrane and potentially disrupting the cell membrane of some of the cells in the area.
One of the theories of ultrasound phoresis postulates that the main factor is increasing the permeability of a skin by creating lipid bridges between keratin layers in stratum corneum.
Another important factor that may affect drug diffusion is related to the shear forces (or shock waves) that occur when adjacent portions of the same membranous structures vibrate with different displacement amplitudes. The acoustic waves cause streaming and/or cavitation in the drug medium and the skin layers, which helps the drug molecules to diffuse into and through the skin. “Streaming” is essentially oscillation in a liquid that forces the liquid away from the source of the energy, while “cavitation” is the formation of bubbles in a liquid that is subjected to intense vibration. Cavitation is the result of rarefaction areas during propagation of longitudinal acoustic waves in the liquid when the waves have an amplitude above a certain threshold.
When these bubbles occur in specific cells of the skin, fatigue or rupture of the cells can occur as the bubbles reach an unstable size. Destruction of cells in the transmission path of the ultrasound may facilitate intercellular diffusion of drug molecules. Cavitation may also destruct the organization of lipids in the stratum corneum, resulting in an increase in the distance between the lipid layers. As a result, the amount of waster phase in the stratum corneum increases thereby enhancing the diffusion of water-soluble components through the intercellular space (Mitragotri et al (1995) J. Pharm Sci. 84: 697-706). As the permeation pathway for topically applied products is mainly along the tortuous intercellular route, the lipids in the stratum corneum play a crucial role in proper skin barrier function.
The use of ultrasound to enhance the transport of a substance through a liquid medium is referred to as sonophoresis or phonophoresis. It may be used alone or in combination with other enhancers, such as chemical enhancers, iontophoresis, electroporation, magnetic force fields, electromagnetic forces, mechanical pressure fields or electrical fields.
Ultrasound is applied via a sonotrode, also termed an acoustic horn. The sonotrode serves various functions such as conversion of the acoustic waves, by increasing the amplitude of the oscillations, modifying the distribution and matching acoustic impedance to that of the substrate. Resonance of the sonotrode, which increases the amplitude of the acoustic wave, occurs at a frequency determined by the characteristics of modulus elasticity and density of the material from which the sonotrode is made, the speed of sound through the material and the ultrasonic frequency. The size and shape (round, square, profiled) of a sonotrode will depend on the quantity of vibratory energy and a physical requirements for each specific application.
The use of sonophoresis to enhance the transdermal delivery of medicaments is known and described in various patent documents, including U.S. Pat. No. 6,322,532, U.S. Pat. No. 6,575,956, U.S. Pat. No. 7,737,108, US 2004/210184 and US 2009/155199.
There is an ongoing need for improved devices and methods to enhance transdermal medical and cosmetic compound delivery. In particular, there is an ongoing need for ultrasound-based devices and techniques for transdermal drug or cosmetic delivery.
The most popular sonotrode is a linear taper as shown in FIG. 1 of the accompanying drawings. This shape is simple to make but its potential magnification is limited to a factor of approximately four-fold. The variation of the amplitude of vibration along the length of the sonotrode for this shape is shown in FIG. 1a. 
An alternative design employs an exponential taper as shown in FIG. 2. The amplitude of vibration for this shape of sonotrode is shown in FIG. 2a. This design offers higher magnification factors than a linear taper but its curved shape is more difficult to make. However, its length, coupled with a small diameter at the working end makes this design particularly suited to micro applications.
It is also known to use a stepped design as shown in FIG. 3, in which there is an abrupt transition from the diameter of the proximal portion coupled to the sound generator and the distal portion applied to the substrate. The variation of amplitude for this shape of sonotrode is shown in FIG. 3a. In this stepped design, the magnification factor is given by the ratio of the end areas and the potential magnification is limited only by the dynamic tensile strength of the sonotrode material. This is a useful design and easy to manufacture, while gains of up to 16-fold are easily achieved.
Sonotrodes connected to ultrasound transducers, especially those employed for transdermal delivery of drugs, typically have a length L, expressed by the equation L=n(λ/2), where λ is the wavelength of the ultrasound in the sonotrode and n is a positive integer. In this case, the maximum amplitudes of the acoustic wave are found at the proximal end of the sonotrode and at the λ/2 length beyond the foot of the sonotrode.
Burning and abrasion of the epidermis is also a serious consideration when using ultrasound. Ultrasound should act as a mechanical pressure agent without destructing the epidermis of the skin. However, cavitation in the liquid coupling the sonotrode to the skin may produce cavitation erosion of the epidermis and the dermis. While this cavitation assists with active penetration of the substance being delivered, such cavitation may also destruct the epidermis.
A further challenge when using ultrasound is that it is low in efficiency due to cavitation in the buffer suspension and the low acoustic pressure and ultrasonic energy that is required to prevent burning and other injury.